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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.16 mg/m³
Most sensitive endpoint:
carcinogenicity
DNEL related information
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.704 mg/m³
Most sensitive endpoint:
neurotoxicity
DNEL related information
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.16 mg/m³
Most sensitive endpoint:
carcinogenicity
DNEL related information
Overall assessment factor (AF):
12.5
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.704 mg/m³
Most sensitive endpoint:
neurotoxicity
DNEL related information
Overall assessment factor (AF):
12.5
Dose descriptor starting point:
NOAEC

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.584 mg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
12.5
Dose descriptor:
other: NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.584 mg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
12.5
Dose descriptor starting point:
other: NOAEL

Workers - Hazard for the eyes

Additional information - workers

ACUTE:

 

Table 7-1:Available acute dose descriptors per endpoint for MKH 3586 as a result of its hazard assessment

Endpoint

Quantitative dose descriptor (appropriate unit) or qualitative assessment

Associated relevant effect

Remarks on study

Local

Systemic

Acute toxicity

oral

NA

NOAEL
10 mg/kg

Local: no effects

Systemic: Ptosis, decreased approach response, nasal staining

Acute rat neurotoxicity study

dermal

NOAEL
7.3 mg/cm2

NOAEL 1000 mg/kg

Local: No observed effect

Systemic: No observed effect

28 day rat dermal study

inhalation

Not tested

-

-

-

 

Acute and repeat (sub-acute, sub-chronic, chronic) dermal:

Local-

Dose descriptor selection: from the sub-chronic dermal toxicity study no local effects were observed up to the limit dose (1000 mg/kg/day). The NOAEL value was converted to mg/cm2value based on the quantity of test material applied to the test area of skin (for the repeat dermal rat study a dose area of no less than 10% of the total body surface area (TBSA) was used. The 10% TBSA was considered equivalent to 36 cm2(<250g); 40 cm2(251-300g); 44 cm2(301-350g); 48 cm2(351-400g); 52 cm2(401-450g); 56 cm2(451-500g). For the purposes of DNEL setting the following values for both weight and 10% TBSA were used: 351g and 48 cm2, respectively.

 

NOAEL = dose (mg/kg bw) * bw (g) / 1000g / skin area (cm2).

Sub-acute NOAEL = 1000 mg/kg bw * 351g / 1000g / 48 cm2

Corrected sub-acute NOAEC (local) = 7.3 mg/cm2

 

Dose response: no local effects were observed up to the maximum dose tested, 1000 mg/kg/day (i.e. the NOAEL).

 

AF: default AFs were applied, according to the guidance in Chapter R.8 (note allometric scaling not relevant for local effects).

AF = Interspecies * Intraspecies (worker) * Exposure duration * Dose-response * Quality of whole database

AF = 2.5 * 5 * 1 * 1 *1 = 12.5

DNEL derivation: NOAEC / AF

Repeat (sub-acute, sub-chronic, chronic) DNEL dermal local DNEL = 7.3 mg/cm2/ 12.5 = 0.584 mg/cm2

 

Systemic-

Dose descriptor selection: the lowest reliable dose descriptor was selected from the sub-acute (21 day) dermal study.

Dose response: no systemic effects were observed up to the maximum dose tested, 1000 mg/kg/day (i.e. the NOAEL).

AF: default AFs were applied, according to the guidance in Chapter R.8.

AF = Interspecies (including allometric scaling for rabbit to human) * Intraspecies (worker) * Exposure duration * Dose-response * Quality of whole database

AF = 2.5 *(4) * 5 * 1 *1 *1 = 50

DNEL derivation: NOAEL / AF

- Repeat (sub-acute, sub-chronic, chronic) DNEL dermal systemic = 1000 mg/kg / 50 = 20 mg/kg

 

From the available acute and sub-acute dermal toxicity data the duration of the study does not markedly increase the local or systemic effects, implying that dermal absorption is minimal. Therefore, the acute DNELs for local and systemic effects are considered applicable for the both a sub-chronic and chronic exposure scenario without the need to apply further AF for duration extrapolation.

 

Acute inhalation:

Local and systemic -

Dose descriptor selection: in the acute inhalation study no local effects associated with respiratory irritation or evidence of systemic toxicity were observed immediately after dosing or up 14 day post dosing in this limit study. As there are deficiencies recognised in the study design (i.e. no true NOAEL identified), in accordance with the guidance oral data is available from the acute neurotoxicity study where complete neuro-histopathology was undertaken. The NOAEL derived from this study was in agreement with the NOAEL derived from the two-generation (6.4 mg/kg) and developmental study (15 mg/kg). 

The acute oral neurotoxicity value was corrected in accordance with guidance (Chapter R.8) for route to route (oral to inhalation conversion):

 

Corrected: NOAEC = oral NOAEL * 1 / rat resp. volume (0.38 m3[8 hr]) * oral (50% default) / inhalation absorption (100% default) * human resting resp. volume (6.7 m3[8 hr]) / worker resp. volume (10 m3[8 hr])

 

Acute = NOAEL = 10 mg/kg (NOAEL from acute oral neurotoxicity)

Corrected acute NOAEC = 8.8 mg/m3

 

Dose response: the systemic effects observed in the acute oral neurotoxicity study were deemed to have a threshold mechanism. AF were applied according to the guidance in Chapter R.8.

 

AF: default AFs were applied, according to the guidance in Chapter R.8 (note allometric scaling not relevant for the inhalatory route of exposure). Due to the lack of detailed histopathology and only LD50value established in the acute inhalatory study:

AF = Interspecies * Intraspecies (worker) * Exposure duration * Dose-response * Quality of whole database

AF = 2.5 * 5 * 1 * 1 * 1 = 12.5

DNEL deviation: Corrected NOAEC / AF

- Acute DNEL inhalation local & systemic = 8.8 mg/m3/ 12.5 = 0.704 mg/m3

 

Table 7-2:Acute DNELs for workers

Endpoint Specific DNELs for Workers

Endpoint

Corrected dose-descriptor

Overall AF

Endpoint Specific DNEL

Local

Systemic

Local

Systemic

Acute toxicity

Oral

Not required

Not required

-

-

-

Derm

NOAEL 7.3 mg/cm2

NOAEL

1000 mg/kg

Local 12.5
Systemic 50

0.584 mg/cm2

20 mg/kg

Inhal

-

NOAEC
8.8 mg/m3

Local / systemic 12.5

0.704 mg/m3

0.704 mg/m3

 

 

REPEAT:

 

Table 7-3:Available repeat dose descriptors per endpoint for MKH 3586 as a result of its hazard assessment

Endpoint

Quantitative dose descriptor (appropriate unit) or qualitative assessment

Associated relevant effect

Remarks on study

Local

Systemic

Repeated dose toxicity

sub-acute/ sub-chronic/ chronic

oral

NA
No local tumours

NOAEL
2.3 mg/kg/day

Local: no effects

Systemic: Increased liver weights and biochemical changes (increases in T3, T4 and serum cholesterol)

Chronic phase of 2 year rat combined chronic/ carcinogenicity study

dermal
(sub-acute)

NOAEL

1000 mg/kg

NOAEL

1000 mg/kg

Local: 12.5

Systemic: 50

21 day dermal toxicity study

dermal
(sub-chronic / chronic)

Not tested

-

-

-

Inhalation (sub acute)

Not tested

-

-

-

Inhalation (sub-chronic / chronic)

Not tested

-

-

-

 

Repeat (chronic) dermal:

Refer to the Acute section (above)

 

Repeat (chronic) inhalation:

Local / systemic -

Dose descriptor selection: no repeat dose inhalation study was available, therefore the calculated NOAEC for the inhalatory route has been derived from the guidance for route to route (oral to inhalation) conversion in Chapter R.8 which incorporates a conversion for rat to human respiration volume and an adjustment for work respiration volume.

As oral data is available for sub-acute, sub-chronic and chronic durations, in accordance with the guidance, the chronic oral study is the preferred starting point, with no AF for duration extrapolation required. In this case the NOAEL from the 1 year rat dietary study was used.

 

Corrected: NOAEC = oral NOAEL * 1 / rat resp. volume (0.38 m3[8 hr]) * oral (50% default) / inhalation absorption (100% default) * human resting resp. volume (6.7 m3[8 hr]) / worker resp. volume (10 m3[8 hr])

 

Chronic = NOAEL = 2.3 mg/kg/day (NOAEL from 1 year rat study)

Corrected chronic NOAEC = 2.0 mg/m3

 

Dose response: the systemic effects observed in the chronic oral study were deemed to have a threshold mechanism. AF were applied according to the guidance in Chapter R.8.

 

AF: Default AFs were applied, according to the guidance in Chapter R.8 (note allometric scaling not relevant for the inhalatory route of exposure).

AF = Interspecies * Intraspecies (worker) * Exposure duration * Dose-response * Quality of whole database

 

AF = 2.5 * 5 * 1 * 1 *1 = 12.5

DNEL deviation: Corrected LOAEC / AF = 2.0 mg/m3/ 12.5

Chronic DNEL inhalation local & systemic = 0.2 mg/m3

 

Table 7-4:Chronic DNELs for workers

Endpoint Specific DNELs for Workers

Endpoint

Corrected dose-descriptor

Overall AF

Endpoint Specific DNEL

Local

Systemic

Local

Systemic

Repeated dose toxicity

sub-acute/ sub-chronic/ chronic

Oral

Not required

Not required

-

-

-

dermal
(sub-acute / sub-chronic / chronic)

NOAEL
7.3 mg/cm2

NOAEL
1000 mg/kg/day

Local 12.5 Systemic 50

0.584 mg/cm2

20 mg/kg

Inhalation (chronic)

-

NOAEC
2.0 mg/m3

Local / Systemic
12.5

0.16 mg/m3

0.16 mg/m3

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

As the general population will not be exposed, DNEL considered unnecessary